FGF-4 and BMP-2 have opposite effects on limb growth

Nature. 1993 Jan 7;361(6407):68-71. doi: 10.1038/361068a0.


Limb development is dependent on epithelial-mesenchymal interactions. The apical ectodermal ridge (AER), a specialized epithelium at the limb tip, stimulates proliferation of underlying mesenchyme, causing directed limb outgrowth (for review see ref. 2). Several genes are expressed in the mouse AER, including Fgf-4 (fibroblast growth factor-4) and Bmp-2 (bone morphogenetic protein-2), both of which encode secreted signalling molecules. Using a culture system developed to explore the function of molecules produced by the AER, we have shown that FGF-4 protein stimulates proliferation of mesenchyme in the early mouse limb-bud. This suggests that FGF-4 serves that major function of the AER. In contrast, BMP-2 inhibits limb growth, suggesting that as a result the AER may serve a hitherto unrecognized inhibitory function. Furthermore, the extent of limb outgrowth can be modulated by mixing the two signalling molecules, suggesting that limb growth is regulated by a combination of stimulatory and inhibitory signals from the AER.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins
  • Culture Media, Serum-Free
  • Culture Techniques
  • Extremities / embryology*
  • Fibroblast Growth Factor 4
  • Fibroblast Growth Factors / physiology*
  • Gene Expression
  • Gene Expression Regulation / drug effects
  • Growth Substances / physiology
  • Mice
  • Proteins / physiology*
  • Proto-Oncogene Proteins / physiology*
  • Signal Transduction


  • Bone Morphogenetic Proteins
  • Culture Media, Serum-Free
  • Fgf4 protein, mouse
  • Fibroblast Growth Factor 4
  • Growth Substances
  • Proteins
  • Proto-Oncogene Proteins
  • Fibroblast Growth Factors